A large body of evidence in animal models indicates that supplementation of the diet or drinking water with inorganic selenium in the form of sodium selenite protects against cancer induced by a variety of chemical carcinogens, including cancer of the colon, mammary gland, pancreas, to cite a few. These data have resulted in considerable interest in the potential of selenium as a chemopreventive agent.
Although inorganic selenium has been shown to inhibit carcinogenesis, there is a concern about its toxicity. On a molar basis, selenium salts are the most toxic among the essential elements. Generally, chronic feeding of 5 to 10 ppm of selenium is toxic in animals. Toxic reproductive and teratogenic effects of selenium have been reported for both animals and humans.
Since selenium occurs predominantly as an organic form (selenomethionine) in cereals, vegetables, and grains, attention has been focused to study the effect of organic forms of selenium in carcinogenesis. In methylnitrosourea or 7, 12-Dimethylbenz[a]anthracene induced mammary carcinogenesis, dietary inorganic selenium (4 to 6 ppm) provided greater inhibition of mammary carcinogenesis in female rats than did an equivalent amount of selenium in the form of selenomethionine (Thompson, H. J., Meeker, L. D., and Kokosa, S. Effect of an inorganic and organic forms of dietary selenium on the promotional stage of mammary carcinogenesis in the rat. Cancer Res., 44: 2803-2806, 1984.) In addition, 6 ppm selenium in the form of selenomethionine caused liver damage as indicated by extensive necrosis and fibrosis. Ibid. These observations have shown the need to identify and develop novel forms of organoselenium compounds that are less toxic and more effective than inorganic forms and that can be used effectively as chemopreventive agents. While it has been recognized that synthetic organoselenium compounds offer greater promise for the chemoprevention of cancer, in that their chemical structures can be tailored to provide maximal chemopreventive efficacy with minimal toxicity, the identification and development of a novel selenium compound that is less toxic than previously identified compounds and that possesses tumor-inhibitory effect against colon carcinogenesis has not heretofore been made.
Previously, one of the inventors synthesized two organoselenium compounds, p-methoxybenzenenselenol ("MBS") and benzylselenocyanate ("BSC"), which were found to be effective inhibitors of benzo(a) pyrene-induced forestomach tumors in mice (El-Bayoumy, K. Effect of organoselenium compounds on induction of mouse forestomach tumors by benzo(a)pyrene. Cancer Res., 45: 3631-3635, 1985.) Feeding of 50 ppm MBS in a semipurified diet containing high fat 2 wk before, during, and 1 wk after carcinogen treatment inhibited azoxymethane ("AOM")-induced colon, kidney, and hepatocarcinogenesis in rats. (Reddy, B. S., Tanaka, T., and El-Bayoumy, K. Inhibitory effect of dietary p-methoxybenzeneselenol on azoxymethane-induced colon and kidney carcinogenesis in female F344 rats. J. Natl. Cancer Inst., 74: 1325-1328, 1985; Tanaka, T., Reddy , B. S., and El-Bayoumy, K. Inhibition by dietary organoselenium p-methoxybenzeneselenol, of hepatocarcinogenesis induced by azoxymethane in rats. Jpn. J. Cancer Res. (Gann), 76: 462-467, 1985). It has now been found that BSC in the diet significantly inhibits the incidence and multiplicity of adenocarcinomas in the colon and multiplicity of adenocarcinomas in the small intestine.